Drug discovery may utilise, for screening, a library in which individual compounds are single isomers. This generates 3-dimensional information that can be enhanced by applying computational methods for lead optimisation. In order to prepare single isomer libraries, the appropriate chiral scaffold precursors should be in isomerically pure form, in which relative and absolute configuration is defined across all stereogenic centres. It is equally important that, for a scaffold having a particular bond connectivity, all possible stereoisomers can be prepared. Thus a series of scaffolds of this type can be elaborated chemically into different but defined directions of 3-D space, to give isomeric compounds which may have very different properties in a chiral biological environment.
An important consideration in the development of synthetic routes towards scaffolds is that the chemistry should have the potential for scale-up. Then, in the event that the library screens generate useful lead compounds, the appropriate scaffold can be produced in sufficient quantity to support any subsequent drug discovery and development.
Pipecolic acid and 4-hydroxypipecolic acid are natural non-proteinogenic amino acids found in plants. In addition to the free amino acid, pipecolic acid is also found in complex biologically active molecules (for an example, see Nicolaou et al.; J. Am. Chem. Soc. 1993, 115, 4419–4420). Derivatives of pipecolic acid are known to display anaesthetic (GB-A-1166802), NMDA agonist and antagonist (Ornstein et al.; J. Med. Chem. 1989, 32, 827–833), anticoagulant (Okamoto et al.; Biochem. Biophys. Res. Commun. 1981, 101, 440446) and glycosidase activity (Bruce et al.; Tetrahedron 1992, 46, 10191–10200). Pipecolic acids have also been used in peptide chemistry as analogues of proline (Copeland et al.; Biochem. Biophys. Res. Commun. 1990, 169, 310–314). In the light of the diverse activities displayed by such pipecolic acid derivatives, single enantiomer libraries using such compounds as the scaffold would be a highly desirable tool for screening.
For a recent review of the synthesis of pipecolic acids, see Couty, Amino Acids 1999, 16, 297–320. A common synthetic route to racemic 4-hydroxypipecolic acid derivatives, has been to use an acyliminium ion cyclisation on a suitably protected homoallylic amine (Hays et al.; J. Org. Chem. 1990, 56, 4084–4086). This approach has been adapted to furnish enantiomerically pure cis 4-hydroxypipecolic acid derivatives provided a chiral protecting group is used in the synthesis (Beaulieu et al.; J. Org Chem. 1997, 62, 3440–3448). However, the protecting group does not offer any asymmetric induction, and the enantiomers have to be separated by a laborious co-crystallisation with (−)-camphorsulphonic acid. A similar approach to the synthesis reports a separation by recrystallisation of a diastereoisomeric intermediate (Skiles et al.; Bioorg. Med. Chem. Lett. 1996, 6, 963–966).
Another common theme in the synthesis of enantiomerically pure cis 4-hydroxypipecolic acid derivatives has been to fix the stereochemistry of the carboxylate group using a (L)-aspartic acid, and use this stereocentre to direct reduction of a ketone at the 4-position (Golubev et al.; Tetrahedron Lett. 1995, 36, 2037–2440; Bousquet et al.; Tetrahedron 1997, 46, 15671–15680). Two routes derived from carbohydrate starting materials have been reported, an atom inefficient synthesis starting from D-glucoheptono-1,4-lactone (Di Nardo and Varela; J. Org. Chem. 1999, 64, 6119–6125) and from D-glucosamine (Nin et al.; Tetrahedron 1993, 42, 9459–9464). All of these approaches yield only the cis-diastereoisomer. In particular, it remains a challenge to synthesise the two stereoisomers of trans-4-hydroxypipecolic acid in conveniently protected form, especially the N-Boc derivatives (i) and (ii)

The most common approach has been to synthesise the cis-diastereoisomer, followed by a tedious inversion of the 4-hydroxy group. An alternative approach has utilised a ring expansion of 4-hydroxy-L-proline (Pellicciari et al.; Med. Chem. Res. 1992, 2, 491–496) and provides access to both diastereoisomers of 4-hydroxy-L-pipecolates. However, this route is unattractive on a large scale, owing to the two chromatographic steps needed for the separation of regio- and diastereomeric mixtures, and also the requirement for the hazardous reagent ethyl diazoacetate to effect ring expansion.
Both enantiomers of 2-acetamidopent-4-enoic acid are readily available in large quantities via bioresolution of a racemic mixture, and as such are valuable chiral building blocks. Using standard literature chemical methods, it is possible to convert both enantiomers of suitably protected 2-acetamidopent-4-enoic acid into mixtures of diastereoisomers (A) and (B)

These diastereoisomeric ester mixtures (A) and (B) may be convenient intermediates for the preparation of scaffolds if their separation could be readily achieved. Although selective crystallisation can often provide a simple means to achieve scaleable separation of diastereoisomers, this technique is not applicable to mixtures (A) and (B), which are obtained as oils.
There are isolated reports in the literature that biocatalysis can be used as a means to effect separation of diastereoisomeric mixtures. For example, see Wang et al.; J. Org. Chem., 1998, 63, 4850–3; Hiroya et al.; Synthesis, 1995, 379–81; Mulzer et al.; Liebigs Ann. Chem., 1992, 1131–5.